Target unit with ceramic capsule for producing cu-67 radioisotope

ABSTRACT

A target unit for producing Cu67 radioisotope is described herein, and comprises a cage body releasably coupled to a screw-on cap; and a ceramic capsule containing a solid Zn68 target ingot and having one open end and one closed end and defining an interior chamber for the target ingot. The ceramic capsule is releasably contained between the cage body and the screw-on cap with a lid disposed on the open end of the capsule and a washer positioned between the lid and the screw-on cap. The screw-on cap and the washer provide a water-tight seal between the lid and the capsule. The interior of the capsule is in intimate physical contact with the target ingot; and the Zn68 of the target ingot is free of traces of residual oxygen that interfere with contact of the Zn68 to the capsule.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 15/087,111,filed on Mar. 31, 2016, which is a continuation of U.S. application Ser.No. 13/399,082, filed on Feb. 17, 2012, now U.S. Pat. No. 9,312,037,which claims the benefit of U.S. provisional application Ser. No.61/540,897, filed on Sep. 29, 2011, each of which is incorporated hereinby reference in its entirety.

CONTRACTUAL ORIGIN OF THE INVENTION

This invention was made with government support under Contract No.DE-AC02-06CH11357 awarded by the United States Department of Energy toUChicago Argonne, LLC, operator of Argonne National Laboratory. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

This invention relates to methods and a novel device for producingradioisotopes for medical applications. More particularly, thisinvention relates to methods, as well as novel target units andsublimation devices for producing Cu67 radioisotope.

BACKGROUND OF THE INVENTION

In recent years medical researchers have indicated a desire to exploreradioisotope therapy with beta-emitting sources that may simultaneouslybe monitored by imaging their photon emission. Beta particles withenergies of a few hundred KeV have sufficient range in tissue(millimeters) that they can penetrate small tumor masses, withoutpassing much further into the surrounding body and inadvertentlydestroying healthy tissue. Gamma rays of a few hundred KeV may beconveniently imaged with external cameras. An isotope that emits bothparticles must also have appropriate chemical properties in order toattach the isotope to a biologically active agent, such as a peptide ormonoclonal antibody. Copper-67 (Cu67) has emerged as one of the mostdesired of these new radioisotopes; it emits beta particles with meanenergy of 141 KeV and a gamma ray of 185 KeV. Its half-life of 2.6 days,however, demands rapid production, processing, and transfer to themedical clinic. Therapy of non-Hodgkin's lymphoma is perhaps the mostrecognized application for Cu67, but the dearth of supply has seriouslyinhibited the research effort in this area.

Cu67 has been produced by two main processes, i.e., in nuclear reactorsin small quantities, and by bombardment of zinc oxide (ZnO) with highenergy protons.

In the mid 1990s, Cu67 was produced by irradiation of ZnO inDOE-subsidized high-energy physics proton accelerators, e.g., BLIP atBrookhaven National Lab (BNL) and LAMPF at Los Alamos National Lab(LANL). By 2000, DOE changed its focus, with additional production beingperformed on the proton cyclotron at TRIUMF, in Canada, and import ofthe Cu67 to medical researchers in the United States.

Reactor production of Cu67 is particularly difficult for severalreasons. For example, neutron flux results in a number of harmful,unwanted other isotopes, which are difficult to remove from the desiredCu67. Human medical treatment applications require non-copper impuritiesto be reduced to parts-per-billion (ppb) levels, elimination ofradioisotopes of copper other than Cu67, and a high specific activity(no more than a few hundred stable copper atoms for each Cu67 atom). Inaddition, the reactor method needs a sophisticated mechanical rabbit toretrieve the isotope from the core, and radioactive waste handling iscostly (frequently requiring subsidization by national governments),which generally hinders economic production of radioisotopes.

Linear accelerator (“linac”) production at BLIP and LAMPF wastechnically successful, but the two labs simply could not provide enoughCu67 to meet the demand. Production was limited to a total of about 1 Ciper year, due to scheduling demands on the accelerators for high-energyphysics missions. Also, proton accelerator production requiresirradiation of the target in a vacuum, and the machine must be opened toatmospheric pressure to recover the target, complicating the recovery.

In the past, metal zinc target capsules have been used on electronaccelerators to provide high yields of Cu67 via a photonuclear process(gamma rays from Bremsstrahlung convert Zn68 into Cu67). Zinc materialwas then irradiated, and Cu67 would be separated very quickly andefficiently using a sublimation process. Both the metal casting processinto metal target capsules and subsequent sublimation attempts withmetal apparatus have resulted in unacceptable levels of metalimpurities, which were introduced by corrosive chemical reactions ofzinc in the liquid and vapor phases.

Accordingly, there is an ongoing need for improved methods for producingCu67, particularly having a purity and specific activity suitable formedical applications. The present invention addresses this need.

SUMMARY OF THE INVENTION

The present invention provides a photonuclear method for producing Cu67radioisotope suitable for use in medical applications. The methodcomprises irradiating metallic zinc-68 (Zn68) contained within a closedceramic capsule with a high energy gamma ray beam to convert at least aportion of the Zn68 to Cu67, and then isolating the Cu67 from theirradiated target. During irradiation, at least a portion of the Zn68 isconverted to Cu67 by loss of a proton. Preferably, the irradiation iscontinued until the conversion of Zn68 to Cu67 yields a Cu67 activity ofat least 5 milliCuries-per-gram of target (mCi/g). Our work hasuncovered that composing the target capsule and sublimation apparatusout of ceramic materials that do not chemically react with molten zinc(e.g., alumina, aluminum nitride and boron nitride), and in particularalumina, offers a solution to avoiding the introduction of impuritiesduring casting or sublimation known to take place in prior equipment.

The present invention also provides an improved target unit forproducing Cu67 radioisotopes. It also provides for easier handling andshipping of the target because of its use of low activation materials.The target unit includes a target body having a cage body coupled to ascrew-on cap and a ceramic capsule containing the Zn68 target. Theceramic capsule is sealed within the target body between the cage bodyand the screw-on cap to form a substantially water-tight seal duringirradiation. The ceramic capsule material must be selected to preventchemical reaction with zinc; nevertheless, it must promote a solidphysical contact between the capsule and solid Zn68 target ingot withinthe capsule. Even a small gap between the capsule and the Zn ingot wouldinhibit heat transport out of the zinc during high-power irradiation,resulting in melting and possible failure of the target. For this reasoncertain non-metals, such as graphite and boron nitride, are notappropriate for the target capsule. Alumina is an example of onesatisfactory material of construction for the capsule. The initial stockof Zn68, and any additions of fresh stock to replace losses, must besubstantially free of residual traces of oxygen. Substantiallyoxygen-free zinc promotes good physical contact between the cast ingotand the ceramic capsule. Substantially oxygen-free zinc can be preparedby subliming the Zn68 at least once prior to forming the target ingot.As used herein, the term “substantially oxygen-free zinc” andgrammatical variations thereof, refer to trace oxygen levels within thetarget ingot that are low enough to prevent loss of adhesion between thecapsule and the zinc target ingot during irradiation.

The present invention also provides for an improved apparatus forsubliming the irradiated metallic zinc target material from the Cu67radioisotope. The sublimation apparatus comprises a ceramic sublimationbody, which is a vacuum sealable tube with one open end. A ceramiccapsule containing the irradiated metallic zinc target is placed withinthe sublimation body. The sublimation body is coupled to a vacuumsource, which forms a leak-tight vacuum seal at temperatures betweenapproximately 500 to about 700° C. The ceramic sublimation body materialmust be chosen to prevent chemical reaction with zinc liquid and vapor,but the zinc vapor from sublimation must deposit and physically adhereto the interior of cooler regions of the tube that are not directlyheated. Additionally, upon later heating, the deposited zinc must meltand flow freely for subsequent recovery of the expensive Zn68 to refilland cast a new target ingot within a new capsule. For this reasoncertain non-metals, such as quartz/glass, are not appropriate for thesublimation body. Alumina is one example of a satisfactory material ofconstruction for the sublimation tube.

In addition, the present invention provides an improved method forrecovering the sublimed Zn68 from the sublimation tube. In particular,the open ended ceramic sublimation tube is inverted over a hopper inorder to fill a new ceramic capsule. The inverted sublimation tube andhopper are placed within a hermetic surround and heated in an inertatmosphere. The hopper funnels the molten zinc into the new ceramiccapsule. For this process the hopper must be constructed from anon-metallic material which has no chemical reaction with molten Zn;graphite or glassy carbon are satisfactory materials, which may beeasily fabricated into the desired hopper dimensions to properly alignwith the opening of the tube.

Further details regarding sublimation and irradiation of zinc forproducing Cu67 radioisotope are described in U.S. patent applicationSer. No. 12/462,099, filed Jul. 29, 2009, the disclosure of which isincorporated herein by reference in its entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention consists of certain novel features and a combination ofparts hereinafter fully described, illustrated in the accompanyingdrawings, and particularly pointed out in various aspects of theinvention, it being understood that various changes in the details maybe made without departing from the spirit, or sacrificing any of theadvantages of the described invention.

FIG. 1 depicts an exploded representation of a target unit useful in themethods of the present invention, in partial cross-section.

FIG. 1A depicts an isometric representation of an alternative targetunit design, fully assembled.

FIG. 2 depicts an assembled isometric representation of the target unitof FIG. 1, assembled.

FIG. 3 depicts a top plan view of the assembled target unit of FIG. 1.

FIG. 4 depicts a bottom plan view of the assembled target unit of FIG.1.

FIG. 5 depicts a cross-sectional representation of the sublimationapparatus useful in the methods of the present invention.

FIG. 5A depicts a detailed cross-sectional view of the coupler portionof the apparatus of FIG. 5.

FIG. 5B depicts an isometric representation of an alternative vacuumhead design for the apparatus of FIG. 5, partially disassembled.

FIG. 5C depicts an isometric representation of the alternative vacuumhead design shown in FIG. 5B, fully assembled.

FIG. 6 depicts a cross-sectional representation of the sublimation tubeand hopper useful in the methods of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides a method for producing Cu67 radioisotopecomprising irradiating a metallic Zn68 target with a high energy gammaray beam to convert Zn68 atoms to Cu67, and then isolating the Cu67 fromthe irradiated target.

Preferably, the target to be irradiated comprises at least about 90%Zn68, more preferably at least about 95% Zn68, and even more preferablyat least about 99% Zn68. It is particularly preferred that the Zn68target include as low a level of copper contaminant as is practical, inorder to minimize the amount of cold copper recovered after irradiationto produce radioactive Cu67. Zn68 containing low levels of copper can beobtained, for example, by repeated sublimation or by zone refining ofthe Zn68. At each sublimation stage less than 10% of the small amount ofcopper in the target material is transferred with the sublimed material,thereby affording a higher ratio of radioactive copper to cold copperafter each cycle until substantially all of the cold copper is depletedfrom the zinc.

The quantity, Q1, of initial copper in the bulk zinc target can bemeasured, as can the amount of copper, Q2, left in the sublimed zincdeposit. The metric r=(Q2/Q1)×100% (i.e., the percentage of copper leftin the sublimed zinc) is a figure of merit, which provides an assessmentof the efficiency of the sublimation process for removing trace amountsof copper from the bulk zinc. In six different sublimation runs, thepercentage of copper removed from the zinc during sublimation was in therange of 85 to 99.5% (i.e., values of r=0.5%, r<1.4%, r=2.5%, r=3.6%,and r≤15% were observed). Based on these observations, recycling of thetarget zinc material will likely reduce trace amounts of cold copper byorders of magnitude after a few sublimation cycles. Thus, utilizing Zn68that has been repeatedly sublimed (e.g., Zn68 sublimate recovered fromrepeated runs of the present methods) will lower the level of coldcopper present in the Cu67 obtained after irradiation, and thus increasethe specific activity of the Cu67 in the copper isolated from theprocess. The sublimation processing procedure can thus provide anextremely high specific activity of Cu67. For example, the radioisotopeCu67 product supplied to customers can have fewer than ten cold(nonradioactive, stable) copper atoms for each Cu67 atom. This isequivalent to a specific activity of ≥75 kCi/gram of copper.

The Zn68 target present in the ceramic capsule can be configured in anysuitable and convenient manner. For example, the target can beconfigured in the form of a frustum, a straight cylinder, or any othersuitable shaped solid mass, and the like. The target and capsule canalso be housed in a unit as desired, which preferably provides awater-tight seal for the capsule. The Zn68 within the capsule can be anysolid monolithic ingot in tight contact with the capsule, such as asolid plate, a solid cylinder, or any other suitable configuration. Goodphysical contact between the solid ingot and the capsule can be achievedby pre-sublimation of the zinc to guarantee removal of oxygen from themetal. The target preferably has a mass in the range of about 100 toabout 200 grams, although smaller and larger targets are suitable, aswell.

The Zn68 target is irradiated with a gamma ray beam having an intensityof at least about 1.3 kW/cm2, and comprising gamma rays having an energyof at least about 30 MeV. In a preferred embodiment, the gamma rays areproduced by irradiating a tantalum target (Ta converter) with a highenergy electron beam (e.g., 40-50 MeV, 6-10 kW) from a linearaccelerator. The irradiation produces gamma rays of suitable energy forconverting Zn68 to Cu67. Preferably, the tantalum is irradiated with ahigh power electron beam having a beam energy in the range of about 40MeV to about 100 MeV and a beam current in the range of about 100 toabout 200 microAmperes. Irradiation of the tantalum results inproduction of gamma rays having an energy in the range of about 40 toabout 100 MeV, which is well suited for conversion of Zn68 to Cu67.Preferably, the irradiation is continued until the conversion of Zn68 toCu67 yields a Cu67 activity in the target of at least about 5milliCuries-per-gram of target (mCi/g), more preferably at least about10 mCi/g, even more preferably at least about 20 mCi/g. Typicalirradiation times are in the range of about 24 to 72 hours.

The tantalum converter preferably has a thickness in the range of about1 to about 4 mm and can comprise a single plate of tantalum or multiplestacked plates. Alternative converter materials include tungsten(preferably coated with a thin layer of Ta for chemical stability), orheavier metals such as lead (e.g., encased in a sealed jacket).

The tantalum converter and the Zn68 target can be configured in anysuitable manner within the electron beam of the linear accelerator. Dueto the inevitable heating of the converter and target, cooling may berequired during irradiation to avoid mechanical failure of the target(e.g., melting). Preferably, the converter and target are cooled by arecirculating cooling system (e.g., immersed in a forced-flow coolingwater bath) while in the beam path of the linear accelerator. The targetceramic capsule is mounted in a holder or target unit that is watertight and may include cooling fins in a suitable number and size to aidin dissipating the heat generated during the irradiation, if desired.The target unit or holder with its included target preferably isimmersed within cooling water during irradiation. After irradiation, thelinear accelerator is shut down, the cooling water flow is stopped, andthe target unit is removed for processing to recover the Cu67 therefrom.

FIG. 1 illustrates a partial cross-sectional view of an exemplaryembodiment of target unit 10, which houses the target and capsule duringirradiation. Target unit 10 includes threaded cage body 20 and screw-cap36, which can be screwed together to house capsule 40. Cage body 20 issubstantially cylindrical having a top 22 defining an aperture 24 and anopen male-threaded bottom portion 26, which defines opening 28 sized andconfigured to receive capsule 40. Cage body 20 also definescircumferential oblong apertures 30. A portion 32 of cage body 20between male-threaded bottom portion 26 and apertures 30 defines agroove 35. Capsule 40 includes a closed end 42 and open end 44, togetherdefining target cavity 45. Metal lid 46 includes closed end 48 and openend 50, which is sized and configured to receive open end 44 of capsule40. Gasket 51 is disposed within lid 46 to seal against open end 44 ofcapsule 40. When assembled, closed end 42 of capsule 40 is receivedwithin open end 28 of cage body 20, while lid 46 covers open end 44 ofcapsule 40, with gasket 51 therebetween. Female threaded portion 38 ofscrew-cap 36 is engaged with male threaded portion 26 of cage body 20such that screw-cap 36 and cage body 20 together exert sufficient forceon cap 36 to provide a water-tight seal over open end 44 of capsule 40.Preferably, washer 53 is included between screw-cap 36 and closed end 48of lid 46. In a preferred embodiment, gasket 51 is composed of graphitebecause it is highly resistant to radiation. Gasket 51 may be composedof other materials, excluding those containing copper.

FIG. 2 provides an isometric view of assembled target unit 10. Asillustrated in FIG. 2, screw-cap 36 includes flattened regions 37 toprovide surfaces suitable to facilitate tightening of screw-cap 36 andcage body 20, e.g., by hand or with a wrench. FIG. 3 provides a top planview of target unit 10, while FIG. 4 shows a bottom plan view, andillustrates the positioning of four flattened regions 37 symmetricallyspaced along the circumference of screw-cap 36.

FIG. 1A illustrates an alternative embodiment of target unit 10, inwhich cage body 20 a defines a larger number of apertures 30 a than cagebody 20 of FIG. 1. Apertures 30 and 30 a can be configured in any formor manner desired. The purpose of including apertures 30 or 30 a intarget unit 10 or 10 a is to allow cooling water to contact capsule 40during irradiation to prevent melting or partial melting of the zinctarget ingot during irradiation.

Capsule 40 is a ceramic crucible, and can be constructed of alumina oraluminum nitride, for example, because these materials do not chemicallycombine with zinc. Alumina is preferred because it is inexpensive and isa well-characterized material. Test results have shown that use ofcapsules composed of alumina by the disclosed methods and equipment donot introduce undesirable metal and other impurities into the resultingCu67 in significant amounts. Tests also have shown that the initial zinctarget (or any fresh zinc to make up for losses) should be substantiallyfree from traces of oxygen, e.g., by pre-purifying the zinc bysublimation to eliminate traces of oxygen; this beneficially promotesgood physical contact, after casting, between the cooled solid zincingot and the ceramic capsule. If oxygen is present in the zinc, a gapbetween the capsule and the zinc ingot may form upon cooling of themolten zinc after filling of the capsule. Such gaps can lead toinefficient cooling, and failure of the target. When assembled, a smallexpansion gap, between about 2 and about 3 mm, preferably is providedbetween the zinc ingot and metal lid 46. This gap is sufficient toprovide the zinc with adequate thermal creep to avoid cracking thecapsule as it expands under high-power heating. In other embodiments, asmall zinc foil may be fitted within the gap to allow for currentleakage during electron beam irradiation, from the zinc metal to themetal lid. Tests have shown there is no galvanic corrosion insidecapsule 40 during beam operations.

Cage bodies 20 and 20 a provide physical protection to ceramic capsule40, as well as an interface-connection to the target chamber at theelectron linac. In a preferred embodiment, cage bodies 20 or 20 a andscrew-cap 36 are composed of different alloys of aluminum to minimizethe possibility of thread galling. For example, cage bodies 20 or 20 acan be composed of 6061 Al and screw-cap 36 can be composed of 2024 Al.

The size and configuration of the target unit (e.g., 10 or 10 a) isdictated by the size and configuration of the target chamber and amountof zinc to be irradiated. Thus, the configuration of the target unit maybe varied without departing from the spirit of the invention. While thepreferred embodiment utilizes a cage body, lid having a gasket, washerand screw-cap to secure the capsule within the target unit, fewercomponents may be utilized, provided that a water-tight seal is createdfor the target capsule.

After the Zn68 has been irradiated for a sufficient period of time, theCu67 produced in the target is isolated from the Zn68 by any suitablemethod. For example, the metallic target can be reacted with an acid todissolve the metals and produce a mixture of metal ions (e.g., zinc andcopper ions). The metal ions can then be separated from one another bychemical techniques that are well known in the art, including ionextraction, ion exchange, precipitation of insoluble metal salts, andthe like. Preferably, the zinc is separated from copper by physicalmeans, e.g., sublimation of zinc.

Zinc can be readily sublimed away from copper at an elevated temperatureunder vacuum. In a preferred embodiment, the Cu67 is isolated bysublimation of the zinc at a temperature in the range of about 500 toabout 700° C. under vacuum, preferably at a pressure in the range ofabout 10⁻³ to about 10⁻⁵ Torr, to remove a substantial portion of thezinc and afford a residue containing Cu67. Preferably, at least about90%, 95% or 99% of the zinc is removed by sublimation, more preferablyat least about 99.9%, even more preferably at least about 99.99%, on aweight basis. The Cu67-containing residue preferably is further purifiedby chemical means, such as reaction with an aqueous acid to form asolution of metal ions, followed by ion extraction, ion exchange, or acombination thereof to recover Cu67 ions.

An example of sublimation apparatus 60 for use in the methods of thepresent invention is shown in FIG. 5 and FIG. 5A, in cross-section.Sublimation apparatus 60 comprises sublimation tube 62, capsule 40,coupler unit 66 and vacuum dome 64, which includes port 65 forattachment to a vacuum source. Sublimation tube 62 includes open end 61,which is sized and configured to have similar dimension to open end 63of vacuum dome 64. Coupler unit 66 seals open end 61 of tube 62 to openend 63 of vacuum dome 64, by means of O-rings 86 and 88.

FIG. 5A provides a detailed cross-sectional view of coupler unit 66,which comprises a tubular sheath 68, which is threaded at each end bymale-threaded regions 70 and 72. Rings 74 and 78 include female-threadedregions 76 and 80, which are sized and configured to engagemale-threaded regions 70 and 72 of sheath 68. Washers 82 and 84 arefitted within rings 74 and 78, respectively. O-rings 86 and 88 aredisposed between the ends of sheath 68 and washers 82 and 84 when unit66 is assembled. When rings 74 and 78 are screwed onto sheath 68,O-rings 88 and 86 are compressed between sheath 68 and washers 82 and84. Ring 74 defines an aperture 71 which is sized and configured toreceive open end 61 of sublimation tube 62, while ring 78 definesaperture 79, which is sized and configured to receive open end 63 ofvacuum dome 64. O-rings 86 and 88 are sized to fit tightly against theexterior circumferences of sublimation tube 62 and vacuum dome 64,respectively. When rings 74 and 78 are tightened over sheath 68 withtube 62 and vacuum dome 64 received in apertures 71 and 79, O-rings 86and 88 become compressed against tube 62 and vacuum dome 64 to form avacuum-tight seal between tube 62 and vacuum dome 64.

In use, sublimation apparatus 60 is assembled with capsule 40, whichcontains a solid ingot 90 of irradiated Zn68, and is situated withinsublimation tube 62. Coupler unit 66 is tightened to provide avacuum-tight seal, and the lower portion of tube 62 is heated to atemperature in the range of about 500 to about 700° C., while applying avacuum in the range of about 10⁻³ to about 10⁻⁵ Torr via port 65. Zincfrom ingot 90 sublimes and collects along the inner surface of tube 62in areas that are not heated, leaving behind a residue of Cu67 incapsule 40 at the end of the sublimation process. The heating andsublimation cycle should be sufficiently slow to avoid thermal crackingof sublimation tube 62 as known by those of ordinary skill in the art.After sublimation is complete, heating is ceased, and the apparatus isallowed to cool at a relatively slow rate.

Sublimation tube 62 preferably is composed of a ceramic material, suchas alumina or boron nitride, because there is no chemical reactionbetween the ceramic and the zinc metal during sublimation. As there isno chemical reaction, no impurities are introduced to the Cu67. Thematerial of construction of sublimation tube 62 may vary, provided thatthe selected material does not result in a corrosive chemical reactionwith the Zn68 metal and Cu67 residue. Use of sublimation apparatus 60 isnot limited to sublimation separation of Zn68 metal from Cu67 residue.If the sublimation body is used to sublime other types of materials, thesublimation body may be composed of a different material as known bythose of ordinary skill in the art. Vacuum dome 64 can be composed ofany suitable material, such as glass or metal. In the preferredembodiment, coupler unit 66 is composed primarily of stainless steel,with the exception of the O-rings, which can be any suitable chemicallyresistant polymeric material, such as, e.g., copolymers ofhexafluoropropylene (HFP) and vinylidene fluoride (VDF or VF2),terpolymers of tetrafluoroethylene (TFE), vinylidene fluoride (VDF) andhexafluoropropylene (HFP), and the like, manufactured under thetradename VITON® by DuPont Performance Elastomers LLC. Other materialsof construction may be utilized without departing from the spirit of theinvention provided the chosen material does not result in unwantedcontamination of the sublimed Zn68 and still provides for a leak-tightpressure seal.

FIG. 5B and FIG. 5C provide isometric views of an alternativeconfiguration for the vacuum dome and coupler. FIG. 5B shows the partspartially disassembled, while FIG. 5C shows the dome and couplerattached to each other. Coupler unit 66 b includes sheath 68 b, which isthreaded at one end for engagement with threaded ring 74 b, with anO-ring, not shown, as described above with respect to FIG. 5. Sheath 68b also includes flange 69 b at its other end. Vacuum dome 64 b includesgasket 67 b which is sized and configured to seal against flange 69 b,when open end 63 b of dome 64 b is received within sheath 68 b. Clamp 75is sized and configured to compress gasket 67 b against flange 69 b,forming a vacuum-tight seal. Dome 64 b also includes flanged vacuum port65 b for connection to a vacuum source. In the embodiments shown inFIGS. 5B and 5C, the components (other than the gasket and O-ring)preferably are composed of a metal such as stainless steel.

Test results have shown that the zinc-copper separation created throughuse of the disclosed sublimation apparatus and method is extremelyefficient. Very little Cu67 transports with the sublimed-deposited zincand extremely small amounts of zinc remain behind with the Cu67 in thecapsule. The remaining Cu67 residue, however, can be further purified bydissolution in an acid (e.g., a mineral acid such as sulfuric acid,hydrochloric acid, phosphoric acid, nitric acid, or a combination ofmineral acids). Tests have shown that ceramics, and in particularalumina, have negligible solubility in acids, so substantially noadditional impurities are introduced through the further purification ofthe sublimed zinc by the acid solution.

The sublimed zinc can be further processed to efficiently separate theremaining traces of zinc from the copper using ion exchange with acopper and/or zinc selective ion exchange resin (e.g., a quaternizedamine resin), anion exchange (BioRad AG 1-X8 columns), or a chelating orsolvating extractant, preferably immobilized on an ion exchange resin orsilica substrate, to afford a Cu67 salt of suitable purity and specificactivity for use in human medical applications. In one embodiment, thecopper residue is dissolved in hydrochloric acid and the resulting Cu67ions are purified on a quaternary amine ion exchange resin, as is wellknown in the art (see e.g., Mushtaq, A., Karim, H., Khan, M., 1990.Production of no-carrier-added ⁶⁴Cu and ⁶⁷Cu in a reactor. J. Radioanal.Nucl. Chem. 141, 261-269).

Suitable metal chelating and solvating extractants are well known in theart and include, e.g., the CYANEX® brand extractants available fromCytec Industries, Inc., West Patterson, N.J., which compriseorganophosphorous materials such as organophosphine oxides,organophosphinic acids, and organothiophosphinic acids. Such extractantcan be immobilized on resin or silica beads, as is known in the art.See, e.g., U.S. Pat. No. 5,279,745; Kim et al., Korean Journal ofChemical Engineering, 2000; 17(1): 118-121; Naik et al., Journals ofRadioanalytical and Nuclear Chemistry, 2003; 257(2): 327-332; Chah etal, Separation Science and Technology, 2002; 37(3): 701-716; and Jal etal., Talanta, 2004; 62(5): 1005-1028. The Cu67 recovered after ionexchange typically can be obtained in specific activity of up to 100kCi/g at a purity suitable for human medical use.

The Zn68 sublimate is preferably recycled for use as another target, soas to reduce the level of cold copper contaminant in the Zn68 targetwith each successive recycle, thus affording a radioactive copperresidue containing a higher ratio of Cu67 to non-radioactive copperafter each recycle stage, as described above.

FIG. 6 shows exemplary recycling apparatus 100 to recycle Zn68 sublimate105 for use as another target. Recycling apparatus 100 includessublimation tube 62, hopper 102 and capsule 40 (e.g., as described inFIGS. 1-5). Sublimation tube 62 including Zn68 sublimate 105 on theinterior wall of the tube is inverted and placed over hopper 102. Hopper102 has a substantially cylindrical exterior and includes an internalfunnel 104 configured to deposit molten liquid Zn68 into capsule 40 whensublimation tube 62 is heated to melt the zinc deposited on the interiorof the tube. In the preferred embodiment, hopper 102 is composed of ahigh density, high purity graphite such as POCO; optionally the graphitecan be coated with glassy carbon. Hopper 102, however, may be composedof a variety of different materials provided the material does notchemically react with the liquid zinc.

During use recycling apparatus 100 is placed within a hermetic surround(not shown) as known by those of ordinary skill in the art to create aninert gas structure substantially free of oxygen around apparatus 100.The hermetic surround is then inserted into a furnace or other heatingapparatus so that sublimed zinc 105 melts from sublimation tube 62. Thehermetic surround may be composed of quartz, steel, or any othersuitable material. Hopper 102 directs the molten liquid Zn68 intocapsule 40. In the preferred embodiment, this process is done with aninert gas fill at atmospheric pressure, with temperatures in the rangeof about 450 to about 550° C. Experiments have shown that it is possibleto process and recycle the zinc in the manner described into new targetingots contained within new capsules with negligible loss of the zincmaterial. The melt and fill cycle must be sufficiently slow (about 2 toabout 3° C. per minute heating rate) to avoid thermal cracking of thesublimation tube (e.g., an alumina tube).

Measurements have shown that the target unit disclosed herein results invery low radiation dose rate from the structural materials becausealumina and aluminum are low-activation materials. After linacoperations, the principal radiation hazard is provided by the zinctarget material itself. Operations with enriched Zn68 (>99%) arecharacterized by even lower activation, since Cu67 will be thepredominant isotope, and it has a very soft gamma emission which is easyto shield.

The following example is provided to further illustrate certain aspectsof the present invention, and is not to be construed as limiting theinvention in any way.

EXAMPLE 1 Sublimation of Zinc Target Ingot

Sublimation separation of the irradiated metallic zinc from the Cu67radioisotope was achieved on a zinc target ingot. The solid zinc targetingot within an alumina capsule was placed within a vacuum-tight aluminasublimation tube. The bottom of the sublimation tube was placed into atube furnace and heated under an internal vacuum, to around 700° C. Thesublimed zinc deposited on the cooler top of the sublimation tube, whichwas outside the furnace. Sublimation occurred very rapidly, at aboutgreater than 40 g/h under a modest vacuum of about 1 mTorr. The heatingand sublimation cycle was sufficiently slow, about less than 3° C. perminute, to avoid thermal cracking of the alumina. Once the sublimationprocess was complete, the furnace was shut down and the system wasallowed to cool at a slow rate.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. Allnumerical values obtained by measurement (e.g., weight, concentration,physical dimensions, removal rates, flow rates, and the like) are not tobe construed as absolutely precise numbers, and should be considered toencompass values within the known limits of the measurement techniquescommonly used in the art, regardless of whether or not the term “about”is explicitly stated. All methods described herein can be performed inany suitable order unless otherwise indicated herein or otherwiseclearly contradicted by context. The use of any and all examples, orexemplary language (e.g., “such as”) provided herein, is intended merelyto better illuminate certain aspects of the invention and does not posea limitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A target unit forproducing Cu67 radioisotope comprising: a cage body releasably coupledto a screw-on cap; and a ceramic capsule containing a solid Zn68 targetingot and having one open end and one closed end and defining aninterior chamber for the target ingot; wherein the ceramic capsule isreleasably contained between the cage body and the screw-on cap with alid disposed on the open end of the capsule and a washer positionedbetween the lid and the screw-on cap, wherein the screw-on cap and thewasher provide a water-tight seal between the lid and the capsule; theinterior of the ceramic capsule is in intimate physical contact with thesolid Zn68 target ingot; and the Zn68 of the target ingot is free oftraces of residual oxygen that interfere with contact of the Zn68 to thecapsule.
 2. The target unit of claim 1, wherein the cage body and thescrew-on cap are composed of aluminum.
 3. The target unit of claim 1,wherein the cage body and the screw-on cap are composed of differentalloys of aluminum to minimize the possibility of thread galling.
 4. Thetarget unit of claim 1, wherein the cage body and the screw-on cap areeach composed of different alloys of aluminum selected from the groupconsisting of 6061 Al and 2024 Al.
 5. The target unit of claim 1,wherein the cage body includes apertures to allow cooling water tocontact the capsule during irradiation thereof to prevent melting orpartial melting of the zinc target ingot during the irradiation.
 6. Thetarget unit of claim 1, wherein the ceramic capsule is composed of amaterial selected from the group consisting of alumina and aluminumnitride.
 7. The target unit of claim 1, wherein the capsule is composedof alumina.
 8. A target unit for producing Cu67 radioisotope comprising:a cylindrical cage body with a threaded open end; a screw-on capthreaded to mate with the threaded open end of the cage body; a ceramiccapsule having one open end and one closed end, and defining an interiorchamber containing a Zn68 target ingot in intimate physical contact withthe capsule; a removable lid covering the open end of the capsule; and agasket disposed between the open end of the capsule and the lid; whereinthe ceramic capsule, the lid, and the gasket are arranged within theinterior cavity of the cage body with the lid in contact with thescrew-on cap when the cage body is mated with the screw-on cap, so thatthe screw-on cap applies a pressure on the lid and gasket sufficient toform a water-tight seal over the open end of the capsule when the unitis fully assembled for use; and the Zn68 of the target ingot is free oftraces of residual oxygen that interfere with contact of the Zn68 to thecapsule.
 9. The target unit of claim 8, wherein the cage body and thescrew-on cap are composed of aluminum.
 10. The target unit of claim 8,wherein the cage body and the screw-on cap are composed of differentalloys of aluminum to minimize the possibility of thread galling. 11.The target unit of claim 8, wherein the cage body and the screw-on capare each composed of different alloys of aluminum selected from thegroup consisting of 6061 Al and 2024 Al.
 12. The target unit of claim 8,wherein the cage body includes apertures to allow cooling water tocontact the capsule during irradiation thereof to prevent melting orpartial melting of the zinc target ingot during the irradiation.
 13. Thetarget unit of claim 8, wherein the ceramic capsule is composed of amaterial selected from the group consisting of alumina and aluminumnitride.
 14. The target unit of claim 8, wherein the capsule is composedof alumina.
 15. The target unit of claim 8 wherein the gasket iscomposed of graphite.